Condition médicale (spécialité visée)
Choix aire thérapeutique
Cancérologie / Radio-oncologie/ tumeurs solides
Stades de cancer
Précoce
Biomarqueur
Autre :
Ki-67
Profil des participants
Sexe(s) des participants
Femmes
Aptitude des participants
Majeurs aptes
Critères de sélection
Critères d'inclusion
• Signed Informed Consent Form
• Ability and willingness to comply with all aspects of the study protocol
• Women age 18 years at the time of signing Informed Consent Form
• Histologically confirmed operable or inoperable invasive Stage IIIII BC according to American Joint Committee on Cancer (AJCC) TNM staging classification (Amin et al. 2017; National Comprehensive Cancer Network [NCCN] 2024) with measurable primary tumor 1.5 cm in longest diameter by ultrasound or MRI per mRECIST v1.1
Multifocal tumors (more than one mass confined to the same quadrant as the primary tumor) are allowed if all lesions are sampled and confirmed as ER positive, HER2 negative invasive BC and at least one lesion is 1.5 cm in longest diameter.
Multicentric tumors (multiple tumors involving more than one quadrant) are allowed if all discrete lesions are sampled and confirmed as ER positive, HER2 negative invasive BC and at least one lesion is 1.5 cm in longest diameter.
Individuals with T4d (inflammatory carcinoma) are excluded.
• Candidate for neoadjuvant treatment and considered appropriate for endocrine combination therapy
• Willingness to undergo breast surgery (mastectomy or breast conserving surgery) after neoadjuvant treatment (unless inoperable)
• Willingness to provide mandatory tumor samples as follows:
– Pretreatment
– During treatment on Day 22 ( 2 days) of Cycle 1
– Post-treatment (from surgical specimen) or alternatively a biopsy
• Documented ER-positive tumor in accordance with current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines, assessed locally and defined as 1% of tumor cells stained positive for ER (Allison et al. 2020; use current guidelines if updated) on the most recent tumor biopsy
• Documented progesterone-receptor status (positive or negative) as per local assessment
• Documented HER2 negative tumor in accordance with current ASCO/CAP guidelines, assessed locally (Wolff et al. 2023; use current guidelines if updated) on the most recent tumor biopsy
• Documented Ki-67 score 5% as per local assessment
• Confirmed PIK3CA mutation, as documented through central laboratory testing of a representative formalin-fixed, paraffin-embedded (FFPE) tumor tissue sample by the Roche cobas PIK3CA Mutation Test, which detects the following PIK3CA variants: R88Q, N345K, C420R, E542K, E545X (E545A, E545D, E545G, or E545K), Q546X (Q546E, Q546K, Q546L, or Q546R), M1043I, H1047X (H1047L, H1047R, or H1047Y), or G1049R.
• Postmenopausal or pre/perimenopausal status, defined as follows:
– Postmenopausal, as defined by at least one of the following criteria:
o Documented bilateral surgical oophorectomy ( 14 days prior to first treatment on Day 1 of Cycle 1 and recovery from surgery to baseline)
o Age 60 years and 12 consecutive months with amenorrhea without an alternative medical cause
o Age 60 years and 12 continuous months of amenorrhea with no identified cause other than menopause, estradiol levels and follicle stimulating hormone (FSH) levels in the postmenopausal range
– Premenopausal or perimenopausal, defined as not meeting the criteria for postmenopausal, and willing to undergo and maintain treatment with approved LHRH-agonist therapy for the duration of study treatment
If desired, participants should consider egg banking prior to enrolling in the clinical trial to preserve the potential for future fertility.
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
• Adequate hematologic and organ function within 14 days prior to initiation of study treatment, defined by the following:
– ANC 1.5 109/L (1500/L), with one exception:
Individuals with benign ethnic neutropenia (BEN) are eligible if ANC 1.3 109/L (1300/L).
BEN (also known as constitutional neutropenia) is an inherited cause of mild or moderate neutropenia that is not associated with any increased risk for infections or other clinical manifestations (Atallah-Yunes et al. 2019). BEN is referred to as ethnic neutropenia because of its increased prevalence in people of African descent and other specific ethnic groups.
– Hemoglobin 9 g/dL
– Platelet count 100,000/L
– Adequate renal function (see exclusion criterion on glomerular filtration rate)
– Fasting glucose 126 mg/dL ( 7.0 mmol/L) and HbA1c 6.5% ( 48 mmol/mol)
– Total bilirubin 1.5 upper limit of normal (ULN) ( 3 ULN if Gilbert disease)
– Serum albumin 2.5 g/dL (25 g/L)
– AST and ALT 2.5 ULN
• INR 1.5 ULN (unless the individual is receiving anticoagulants, and the INR is within the therapeutic range of intended use for that anticoagulant) within 14 days prior to initiation of study treatment
• Ability, in the investigator's judgment, and willingness to comply with all study related procedures
• QT interval 450 msec based on mean value of triplicate ECGs corrected through use of Fridericia's formula (QTcF)
Critères d'exclusion
Potential participants are excluded from the study if any of the following criteria apply:
• Pregnant or breastfeeding or intending to become pregnant during the study or within the timeframe in which contraception is required
Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.
• Stage IV (metastatic) BC
• Inflammatory BC (cT4d)
• Bilateral invasive BC
• History of ductal carcinoma in situ or lobular carcinoma in situ if they have received any systemic therapy for treatment or radiation therapy to the ipsilateral breast
Individuals treated with surgery alone may be eligible.
• Immediate surgery is indicated
• Previous systemic or local treatment for the primary BC currently under investigation (including excisional biopsy or any other surgery of the primary tumor and/or axillary lymph nodes, including sentinel lymph node biopsy, radiotherapy, cytotoxic, and endocrine treatments)
– History of any prior treatment with aromatase inhibitors, tamoxifen, selective estrogen receptor degraders, PI3K/AKT/mTOR, or CDK4/6 inhibitors
– Treatment with investigational therapy within 28 days prior to initiation of study treatment
• Currently receiving any of the following substances within 7 days before first dose of study treatment:
Strong CYP3A inhibitors and inducers as well as sensitive CYP3A substrates with narrow therapeutic index
• Systemic chronic corticosteroids 2 weeks prior to starting study treatment or has not recovered from side effects of such treatment
The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops, or local injections (e.g., intra-articular).
• Significant electrolyte abnormalities, including potassium, calcium, and magnesium
• Planned major procedure or surgery during the study, other than those that are part of the planned study procedures
• Substance abuse within 12 months prior to screening
• Malabsorption syndrome or other condition that would interfere with enteral absorption
• Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; or any history of Type 1 diabetes
• Known HIV infection if any of the following apply:
The CD4+ count is less than 350 cells/L.
or
There has been an opportunistic infection within the 12 months prior to the start of study treatment.
or
There is a potential DDI with any of the study treatments
Sites should include an HIV test during screening, if clinically indicated and as allowed per local regulations.
• Known clinically significant and active liver disease, including severe liver impairment (Child-Pugh Class B/C), active viral or other hepatitis, current alcohol abuse, or cirrhosis
Sites should include hepatitis testing during screening, if clinically indicated and as appropriate per local regulations.
Individuals under treatment for hepatitis will be excluded if there is a potential DDI with any of the study treatments .
• Infection requiring IV antimicrobials within 7 days prior to start of study treatment
• Any concurrent ocular or intraocular condition excluding cataracts (e.g., diabetic retinopathy) that, in the opinion of the investigator, would require medical or surgical intervention during the study period to prevent or treat vision loss that might result from that condition
• Active inflammatory (e.g., uveitis or vitritis) or severe infectious (e.g., keratitis, scleritis, or endophthalmitis) conditions in either eye or history of idiopathic or autoimmune-associated uveitis in either eye
• Requirement for daily supplemental oxygen
• Symptomatic active lung disease, including pneumonitis
• Active tuberculosis
• History of or active inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis)
Individuals currently receiving immunosuppressants for inflammatory bowel disease (e.g., sulfasalazines) are considered to have active disease and are thus ineligible.
• Any active bowel inflammation (including diverticulitis)
• Any serious medical condition or abnormality in clinical laboratory tests that precludes an individual's safe participation in and completion of the study
• Prior hematopoietic stem cell or bone marrow transplantation
• Major surgery within 4 weeks prior to first dose of study treatment
• Blood transfusion or hematologic growth factors within the 28 days prior to the start of study treatment
• Estimated glomerular filtration rate (eGFR) 60 mL/min as calculated through use of the Chronic Kidney Disease Epidemiology Collaboration equation and adjusted for body surface area (BSA)
To compute eGFR in mL/min, multiply the eGFR referenced to a BSA of 1.73 m2 with the individual's BSA (calculated using the appropriate Dubois formula) and divide by 1.73 (FDA 2024).
• History of malignancy within 5 years prior to consent, with the exception of the cancer under investigation in this study and malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer
• Clinically significant, uncontrolled heart disease and/or risk factors for ventricular dysrhythmias, including any of the following:
– Myocardial infarction, unstable angina, symptomatic pericarditis, or coronary artery bypass graft within 6 months prior to trial entry
– Cardiomyopathy (e.g., severe left ventricular systolic dysfunction, left ventricular hypertrophy)
– New York Heart Association Class III or IV cardiac disease or congestive heart failure requiring medication
• Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia, complete left bundle branch block, second- or third-degree AV block)
• Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
– Risk factors for torsades de pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
– Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause TdP that cannot be discontinued or replaced by safe alternative medication
– Inability to determine the QTcF interval
• Resistant hypertension defined as the blood pressure of an individual with hypertension that remains elevated above goal despite the concurrent use of three anti hypertensive agents of different classes (Carey et al. 2018; Whelton et al. 2018; Williams et al. 2018; use current guidelines if updated)
• Severe aortic stenosis
• Uncontrolled hypothyroidism
• Known allergy or hypersensitivity to any of the study drugs or any of their excipients
– Hypersensitivity to peanut or soy (due to ribociclib)
• Known issues with swallowing oral medication
• For premenopausal or perimenopausal individuals: known hypersensitivity to LHRH agonists